The treatment of oncogenic lesions residing in bone has advanced with an ever increasing array of therapies;however, response to treatment is considered "unmeasurable" according to existing clinical response criteria (RECIST). Therefore, the biomarkers available for assessment of treatment response used by oncologists and radiologists to monitor the response of cancer in the bone needs a quantum advance. Underlying this need is that bone is a common site of residence of metastatic tumors derived from prostate cancer. Imaging using skeletal scintigraphy, plain radiography, computed tomography, or magnetic resonance imaging remains essential, with positron emission tomography or single-photon emission computed tomography having potential applicability for diagnosing the presence of bone metastases. However, no consensus exists as to the best modality for diagnosing these lesions or for assessing response to treatment. In this application, we hypothesize that changes in tumor microenvironment (e.g. cell density) will occur early following initiation of successful therapy. Since water within tumor cells is in a restricted environment versus extracellular water, loss of cell membrane integrity has been shown to reduce the diffusion barriers (e.g. restrictions) of water within the tumor, which can be quantified using diffusion MRI. We have recently developed the functional diffusion map (fDM) which is an imaging biomarker analytical approach for quantifying therapeutic-induced changes in the Brownian motion of water within tumor tissue. In this application, we will evaluate the capability of the fDM imaging biomarker for quantification of treatment response in a mouse model of metastatic prostate cancer to the bone. Treatments to be evaluated include ionizing radiation, cytotoxic chemotherapy (docetaxel), anti-angiogenic therapy, molecularly targeted agents and androgen deprivation. Animal studies will provide the data needed to support the use of the fDM imaging biomarker for quantification of the effectiveness of key therapeutic interventions. Clinical studies will also be undertaken to assess the fDM biomarker as an early treatment response marker for outcome assessment in patients treated with androgen deprivation or docetaxel chemotherapy. The ultimate goal of this application is to evaluate the fDM method as a viable, quantifiable imaging biomarker for early monitoring o treatment response in patients with metastatic prostate cancer to the bone. PUBLIC HEALTH RELEVANCE: Overall, this research effort will provide further rationale for initiation of clinical studies with combinations of cytotoxic and molecularly targeted therapies for the treatment of bone cancer. In addition, imaging biomarkers for early assessment of treatment response will be evaluated and validated leading to individualization of treatment for bone cancer patients.